Hydrochloric Acid → 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester

HRID 2261712Notes

Reaction equation

HRID 2261712 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:32]([N:34]2[CH:38]=N[CH:36]=[CH:35]2)=[O:33])C=1.Cl.[F:40][C:41]1C=[CH:48][CH:47]=[C:46]2[C:42]=1CNC2.Cl>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@H:9]([C:14](=[O:26])[NH:15][C@:16]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]2[CH:19]=[CH2:20])[CH2:10][C@@H:11]([O:13][C:32]([N:34]2[CH2:35][C:36]3[C:48](=[CH:47][CH:46]=[CH:42][C:41]=3[F:40])[CH2:38]2)=[O:33])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 426096434-Fluoro-1H-isoindoline hydrochlorideHCID 57892908(2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate

Product 1

HCID 576892124-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl esterYield 82.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a solution of 8.19 g of crude (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and 60 mL of toluene was added 4.25 g CDI (26.2 mmol) Sin portions at a temperature of 22-25° C. The reaction mixture was stirred for 1.5 h at RT. Then 3.66 g (21.0 mmol) of 4-fluoroisoindoline hydrochloride was added in portions followed by 3.1 mL of TEA. The resulting suspension was heated to 52° C. bath temperature. After stirring for 3 h at this temperature the reaction mixture was cooled with an ice bath and 70 mL of aqueous HCl (1M) were added. The mixture was extracted with 50 mL of toluene. The separated aqueous layer was extracted twice with 50 mL toluene. The combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of Na2CO3 (5 wt %). The toluene extract was dried (Na2SO4), filtered, and the solvent was completely removed. 9.21 g of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-tert-butoxycarbonyl-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester was obtained as a grey solid, which was used in the next step without further purification.

Workup

  1. temperatureThe resulting suspension was heated to 52° C. bath temperature
  2. stirringAfter stirring for 3 h at this temperature the reaction mixture
  3. temperaturewas cooled with an ice bath
  4. extractionThe mixture was extracted with 50 mL of toluene
  5. extractionThe separated aqueous layer was extracted twice with 50 mL toluene
  6. washThe combined toluene extracts were washed with 30 mL of water and 30 mL of an aqueous solution of Na2CO3 (5 wt %)
  7. extractionThe toluene extract
  8. dry with materialwas dried (Na2SO4)
  9. filtrationfiltered
  10. customthe solvent was completely removed

Sources & evidence

ORD record
ord-177fcd8bcf894bd5ab7a65c17bad4106
Source dataset
uspto-grants-2010_12
Patent number
US07847106B2

Reaction notes

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